Anatomical and physiological evidence for involvement of tuberoinfundibular peptide of 39 residues in nociception.

Laboratory of Genetics, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.

Abstract

The parathyroid hormone 2 (PTH2) receptor's anatomical distribution suggests that, among other functions, it may be involved in modulation of nociception. We localized PTH2 receptor protein to spinal cord lamina II and showed that it is synthesized by subpopulations of primary sensory neurons and intrinsic spinal cord dorsal horn neurons. Tuberoinfundibular peptide of 39 residues (TIP39) selectively activates the PTH2 receptor. Intraplantar microinjection of TIP39 caused a paw-withdrawal response and intrathecal injection caused scratching, biting, and licking, a nocifensive response. Intrathecal administration of a TIP39 antibody decreased sensitivity in tail-flick and paw-pressure assays. Intrathecal administration of TIP39 potentiated responses in these assays. We determined the sequence of TIP39's precursor and found that mRNA encoding TIP39 and TIP39-like immunoreactivity is concentrated in two brainstem areas, the subparafascicular area and the caudal paralemniscal nucleus. Cells in these areas project to the superficial dorsal horn of the spinal cord. Our data suggest that TIP39 released from supraspinal fibers potentiates aspects of nociception within the spinal cord.

Responses to TIP39 administration. (a) Force of the paw-withdrawal response immediately after intraplantar administration of various doses of TIP39. (b) Time spent performing scratching, biting, and licking (SBL) behaviors during the 20 min after intrathecal administration of TIP39.

Modulation of nociceptive responses by intrathecal administration of an antibody to TIP39 or TIP39 itself. Tail-flick (a, d), paw pressure (b, e), and Hargreaves' (radiant heat directed to a paw; c, f) assays were performed as described in Materials and Methods. Responses after intrathecal delivery of vehicle (Veh), antibody to TIP39 (α-TIP), or preimmune serum (Pre Imm) are shown at 30 min after injection, the time at which the largest effect of the antibody was observed (a–c). Responses at various times after injection of vehicle or 100 fmol of TIP39 (TIP39) are shown (d–f).